The Next-Generation Biosimilar Race: A Tale of Two Autoimmune Biologics

To date, prospective biosimilar makers have had plenty of chances to hone their business skills. They have calculated opportunity costs, projected constantly updated financial projections, worked their legal departments and partners overtime, and tested new communication skills with the FDA. Among the factors that manufacturers have to address when deciding on new biosimilar targets: patent dances and mazes, commercialization partners (if they don’t do it themselves), potential competition from other biosimilars, and of course potential risk (i.e., investment) versus reward (i.e., revenue). Overall, this can be a test of both the manufacturers’ and payers’ patience.

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When considering biosimilar targets, it makes sense to follow the money. Focus on today’s high-revenue products that can support acceptable sales for multiple competitors. In other words, one cannot expect to obtain approval and remain the sole biosimilar manufacturer for a product with annual US sales of $1.5 billion.

The autoimmune space is one of most lucrative in terms of pharmaceutical sales. To a great degree, this is attributable to the performance of Humira®, Enbrel®, and Remicade®. However, the later wave of entrants, including other TNF-inhibitors and the interleukin products have also posted sales of $1 billion or more.

This article addresses two specific products with impending patent expirations, one with multiple potential biosimilars and one without. The biosimilar candidates are not listed in any particular order or ranking.

USTEKINUMAB (STELARA®) BIOSIMILARS IN DEVELOPMENT

The main patent for Stelara expires in September 2023 in the US (January 2024 in Europe). Whereas the US sales of Janssen’s product were a prodigious $4.3 billion in 2019, EvaluatePharma estimated that this could be 80% higher (or $7.8 billion) by the time of patent expiration. On that basis alone, it should be a highly attractive target for biosimilar development.

Ustekinumab is an interleukin 12/23 inhibitor, and it was first approved in September 2009 for the treatment of plaque psoriasis, after an initial filing in 2007 and FDA complete response letter in 2008. Janssen received subsequent approvals for psoriatic arthritis and Crohn’s disease. Janssen has filed 54 patents on the reference product.

Formycon AG. Formycon partnered with Aristo Pharma GmbH on the manufacture and testing of this interleukin 12/23 inhibitor (also known as FYB 202). This product is in early-stage analytic evaluation.

Celltrion. Experienced biosimilar player Celltrion seems to have begun phase 1 trials earlier this month for its ustekinumab biosimilar candidate CT-P43, The trial of 270 healthy volunteers, which will include US- and EU licensed versions of Stelara, is scheduled for completion in February 2021. Interestingly, Celltrion does not include this investigational biosimilar on its pipeline page.

NeuClone Pharmaceuticals. Australian firm NeuClone has a biosimilar product (referred to as NeuLara). According to the company, it has successfully passed the analytical and characterization stage of development and has obtained positive preliminary results of its phase 1 study (though not listed in http://www.clinicaltrials.gov). This study included 200 healthy volunteers who received doses of the biosimilar or US- or EU-licensed Stelara. The final clinical study report is anticipated in the third quarter of 2020.

Bio-Thera Solutions. Bio-Thera Solutions, based in Guangzhou, China, has just begun a phase 1 clinical study on its biosimilar BAT2206. It is not clear whether the biosimilar, if successful, will be commercialized in the US, and with any potential marketing partner.

Alvotech. Only recently announced, Alvotech had signed a commercialization agreement with Teva on its full pipeline of 6 biosimliars, including adalimumab, and likely, ustekinumab. There is no indication as to whether Alvotech’s potential biosimilar has made it past the analytic and characterization stage of development.

Celerion AG. A poster presented by Celerion in 2018 announced a successful evaluation of similarity between an investigational biosimilar ustekinumab and the reference product (EU and US versions). However, it is unknown as to whether this product was developed by Celerion or the study was completed on behalf of another manufacturer. Celerion’s primary role seems to be that of a contract research and manufacturing organization.   

CERTOLIZUMAB PEGOL (CIMZIA®): ANOTHER STORY

First approved in April 2008 for the treatment of moderate to severe Crohn’s disease, UCB’s Cimzia (certolizumab pegol) patent expires in the US in 2024 (2021 in the UK). The product is PEGylated anti-TNF-alpha antibody (more precisely, a PEGylated Fab fragment).

In 2019, UCB received approval for use of Cimzia in nonradiographic axial spondyloarthritis. It was subsequently approved for the treatment of rheumatoid arthritis, plaque psoriasis, UC, adults with active psoriatic arthritis, and adults with active ankylosing spondylitis. It is not indicated for use in pediatric patients.

There seems to be little difference in efficacy or safety outcomes between certolizumab and adalimumab for the treatment of rheumatoid arthritis.

Eons ago (in 2017), only one prospective biosimilar manufacturer (Pfenex) had indicated certolizumab was part of its pipeline. Today, even that may not be the case. Pfenex is no longer playing in this space (and in fact, Ligand announced on August 10 that it would purchase Pfenex) , and a search for publicly available information reveals only one biosimilar in preclinical trials (from Xbrane). It is not yet known if Xbrane intends to market the product in the US (it announced an agreement with STADA in May 2019 for commercialization of the biosimilar in the EU and other countries). We may assume that Xbrane would likely partner with another company if it is to commercialize the drug in the US as well.  

For the first half of 2019, UCB reported US sales of Cimzia of approximately $560 million, with global sales of $915 million. This would put annual US sales at around $1.1 billion. By 2024, estimates put that figure closer to $2 billion in the US alone. Drug Patent Watch indicates that UCB has 85 patents associated with the agent.

Although the sales figures are rather modest next to behemoths in the autoimmune space like Humira and Enbrel, it should certainly have an appeal to biosimilar manufacturers. However, there is a curious lack of interest (publicly stated interest, anyway) for this reference product. Joshua Whitehall at Goodwin (publishers of Big Molecule Watch, which he edits) confirmed for us that currently no patent litigation is pending within the US involving Cimzia.

One thing we do know. The competition hasn’t scared anyone off. For now, Xbrane could have a rare, lucrative opportunity in the US market.

(Note: this article was updated on August 18th to include information on Celltrion’s CT-P43).

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